NDUFA2

Chr 5AR

NADH:ubiquinone oxidoreductase subunit A2

Also known as: B8, CIB8, MC1DN13

NCBI Gene: 4695 ENSG00000131495 UniProt: O43678 OMIM: 602137

The encoded protein is a subunit of NADH:ubiquinone oxidoreductase (complex I) in the mitochondrial electron transport chain and regulates complex I activity and assembly through redox processes. Biallelic mutations cause mitochondrial complex I deficiency, nuclear type 13, which presents as Leigh syndrome, an early-onset progressive neurodegenerative disorder. This condition follows autosomal recessive inheritance.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

The encoded protein is a subunit of the hydrophobic protein fraction of the NADH:ubiquinone oxidoreductase (complex 1), the first enzyme complex in the electron transport chain located in the inner mitochondrial membrane, and may be involved in regulating complex I activity or its assembly via assistance in redox processes. Mutations in this gene are associated with Leigh syndrome, an early-onset progressive neurodegenerative disorder. Alternative splicing results in multiple transcript variants.[provided by RefSeq, May 2010]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Mitochondrial complex I deficiency, nuclear type 13MIM #618235

Clinical highlights

Gene–disease validity (ClinGen)

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.61

LOEUF

—

Mechanism

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.61LOEUF

pLI 0.774

Z-score 2.05

OE 0.00 (0.00–0.61)

Moderately constrained

Typical tolerance to LoF variation

Missense Constraint?

-0.24Z-score

OE missense 1.09 (0.89–1.35)

62 obs / 56.9 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.61)

0≤0.351.4

Missense OE?1.09 (0.89–1.35)

0≤0.61.4

Synonymous OE?1.19

0≤1.21.6

LoF obs/exp: 0 / 4.9Missense obs/exp: 62 / 56.9Syn Z: -0.72

Background carrier burden — how many people carry a rare variant somewhere in NDUFA2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 540

161 rare PASS variants

Rare truncating (LoF)

1 in 11,000

29 rare PASS variants

Rare synonymous (reference)

1 in 530

55 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for NDUFA2. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 8 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 290	1 in 20,000
South Asian	~43k	1 in 250	1 in 6,200
Remaining (unassigned)	~30k	1 in 250	≈ 1 in 9,700
European (Finnish)	~27k	1 in 590	≈ 1 in 27,000
Admixed American	~22k	1 in 350	≈ 1 in 5,600
African / African American	~21k	1 in 360	≈ 1 in 9,300
East Asian	~20k	1 in 410	1 in 2,300
Middle Eastern	~2,884	1 in 320	≈ 1 in 2,900

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 3 coding exons well covered in gnomAD exomes and genomes.? see exons ↓